The mission of the Molecular Oncology Program (MO) is to integrate and coordinate research with a focus on identifying and exploring anti-cancer targets, particularly those that distinguish cancer from noncancer cells based on growth, differentiation and survival. Key accomplishments in this Program include the discovery of a novel small molecule that targets an oncogenic fusion protein, STAG2 as a regulator of chromosomal integrity that is deleted in many cancers, and a novel method to chemically reprogram cancer cells. Continued emphasis is on discovering small molecule probes that may lead to future novel therapeutics and biomarkers. To accomplish this mission, MO members perform research around three themes: Theme 1 focuses on unique genomic events that initiate and sustain cancer growth: mechanisms deregulating chromosomal integrity and the role of oncogenic chromosomal translocations in malignancy. Theme 2 focuses on the immortal lives of cancer cells: studies on cellular immortalization; cancer prevention by dietary components that modulate DNA repair mechanisms; and the effect of nutrients on the activity of mutant p53 and its role in transcriptional activation in DNA repair. Theme 3 focuses on the metastatic mechanisms that allow the spread of cancer: discovering novel regulators of metastatic pathways and identifying useful small molecule inhibitors. Led by Jeffrey Toretsky, MD, and Vicente Notario, PhD, the Program has 17 members and includes faculty from six Georgetown University departments. Total peer review funding is $5.9M (direct) in the last budget year, of which $4M is from NCI. MO members published 210 peer-reviewed publications, of which 35% involved external collaborations and 41% were intra- and/or interprogrammatic, the latter involving collaborations with all three other LCCC Programs. Research on small molecules targeting EWS-FLH and the conditionally reprogrammed cells methodology begun in MO have transitioned to the Experimental Therapeutics or Breast Cancer Programs for clinical trials. Members used all nine Shared Resources; MO research on cell immortalization was developed into a new shared service by the Center. The Cancer Center has added value to the Program through $16M in institutional support over the past funding period facilitating the recruitment and support of two new junior faculty members, by facilitating access to new technologies both within the Cancer Center or through external affiliations with other institutions.